TY - JOUR
T1 - Protective antigen antibody augments hemodynamic support in anthrax lethal toxin shock in canines
AU - Barochia, Amisha V.
AU - Cui, Xizhong
AU - Sun, Junfeng
AU - Li, Yan
AU - Solomon, Steven B.
AU - Migone, Thi Sau
AU - Subramanian, G. Mani
AU - Bolmer, Sally D.
AU - Eichacker, Peter Q.
N1 - Funding Information:
Financial support. This work was supported by the National Institutes of Health (NIH) Clinical Center, and a Trans-NIH/Food and Drug Administration Biodefense grant.
PY - 2012/3/1
Y1 - 2012/3/1
N2 - Background. Anthrax-associated shock is closely linked to lethal toxin (LT) release and is highly lethal despite conventional hemodynamic support. We investigated whether protective antigen-directed monoclonal antibody (PA-mAb) treatment further augments titrated hemodynamic support.Methods and Results.Forty sedated, mechanically ventilated, instrumented canines challenged with anthrax LT were assigned to no treatment (controls), hemodynamic support alone (protocol-titrated fluids and norepinephrine), PA-mAb alone (administered at start of LT infusion [0 hours] or 9 or 12 hours later), or both, and observed for 96 hours. Although all 8 controls died, 2 of 8 animals receiving hemodynamic support alone survived (median survival times 65 vs 85 hours, respectively; P=.03). PA-mAb alone at 0 hour improved survival (5 of 5 animals survived), but efficacy decreased progressively with delayed treatment (9 hours, 2 of 3 survived; 12 hours, 0 of 4 survived) (P =. 004 comparing survival across treatment times). However, combined treatment increased survival irrespective of PA-mAb administration time (0 hours, 4 of 5 animals; 9 hours, 3 of 3 animals; and 12 hours, 4 of 5 animals survived) (P =. 95 comparing treatment times). Compared to hemodynamic support alone, when combined over PA-mAb treatment times (0, 9, and 12 hours), combination therapy produced higher survival (P =. 008), central venous pressures, and left ventricular ejection fractions, and lower heart rates, norepinephrine requirements and fluid retention (P ≤. 03).Conclusions.PA-mAb may augment conventional hemodynamic support during anthrax LT-associated shock.
AB - Background. Anthrax-associated shock is closely linked to lethal toxin (LT) release and is highly lethal despite conventional hemodynamic support. We investigated whether protective antigen-directed monoclonal antibody (PA-mAb) treatment further augments titrated hemodynamic support.Methods and Results.Forty sedated, mechanically ventilated, instrumented canines challenged with anthrax LT were assigned to no treatment (controls), hemodynamic support alone (protocol-titrated fluids and norepinephrine), PA-mAb alone (administered at start of LT infusion [0 hours] or 9 or 12 hours later), or both, and observed for 96 hours. Although all 8 controls died, 2 of 8 animals receiving hemodynamic support alone survived (median survival times 65 vs 85 hours, respectively; P=.03). PA-mAb alone at 0 hour improved survival (5 of 5 animals survived), but efficacy decreased progressively with delayed treatment (9 hours, 2 of 3 survived; 12 hours, 0 of 4 survived) (P =. 004 comparing survival across treatment times). However, combined treatment increased survival irrespective of PA-mAb administration time (0 hours, 4 of 5 animals; 9 hours, 3 of 3 animals; and 12 hours, 4 of 5 animals survived) (P =. 95 comparing treatment times). Compared to hemodynamic support alone, when combined over PA-mAb treatment times (0, 9, and 12 hours), combination therapy produced higher survival (P =. 008), central venous pressures, and left ventricular ejection fractions, and lower heart rates, norepinephrine requirements and fluid retention (P ≤. 03).Conclusions.PA-mAb may augment conventional hemodynamic support during anthrax LT-associated shock.
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U2 - 10.1093/infdis/jir834
DO - 10.1093/infdis/jir834
M3 - Article
C2 - 22223857
AN - SCOPUS:84863115426
SN - 0022-1899
VL - 205
SP - 818
EP - 829
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
IS - 5
ER -